Elucidating the chromatin-dependent mechanisms governing chronic inflammatory activation of endothelial cells in atherosclerosis.

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Project Summary and Abstract Despite standard of care, atherosclerotic cardiovascular disease (CVD) remains a leading cause of morbidity and mortality in the United States. In nearly half of patients, risk of CVD is elevated despite adequate control of standard risk factors. In this group, inflammation is proposed as a key driver. Despite this insight, no targeted anti-inflammatory therapies exist for CVD. Thus, an urgent unmet need exists to elucidate novel mechanisms of chronic inflammation in athersclerosis. The long-term goal of my laboratory is to understand how enhancer plasticity drives atherosclerosis through effects on gene expression that change cell state. The overall objectives of this proposal are to 1) to elucidate how inflammatory activation of vascular endothelial cells (ECs) alters EC identity and 2) to define the role of BRD4 in EC activation in atherogenesis. Our central hypothesis is that prolonged inflammatory activation by cytokines and proatherogenic lipids directs a durable remodeling of enhancers such that basal cell state is lost and a new inflammatory cell state is activated. Our hypothesis is formulated on the basis of our previously published work as well as new preliminary data that reveal the following: i) chronic inflammatory stimulation of human aortic ECs (HAECs) results in dynamic activation of a subset of new super enhancers; ii) in HAECs, these new enhancer regions persist despite removing the proinflammatory stimulus; iii) a core transcription factor (TF) circuitry can be inferred from sequence-specific TF motifs that are enriched at chronic inflammatory super enhancers; iv) BRD4 inhibition blocks leukocyte recruitment in peritonitis and atherogenesis in part through EC effects. The rationale for this project is that a deeper understanding of the molecular mediators of chronic inflammation holds the promise of identifying new drug targets designed to reverse the long-term, pathologic activation of vascular cells that drives atherosclerosis. To achieve our overall objectives, we will pursue the following integrated, but non-interdependent specific aims: 1) To determine how chronic, proatherogenic stimuli remodel chromatin structure and unveil new enhancers in human arterial ECs and 2) To determine the functional role of Brd4 in maintaining EC state during atherogenesis in vivo. The overall contribution of this work will be to elucidate how chronic inflammatory signaling establishes a new endothelial cell state through persistent enhancer activation. The central innovation of this proposal is a conceptual shift in research paradigm by demonstrating inflammation drives pathologic cell states in atherosclerosis by a dynamic interplay between chromatin structure, enhancer function and gene expression.